Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive fa...Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.展开更多
Struma ovarii often escapes recognition during intraoperative consultation because of its rarity, subtle characteristic gross appearance, and lack of clinical suspicion. An intraoperative diagnosis of benign struma ov...Struma ovarii often escapes recognition during intraoperative consultation because of its rarity, subtle characteristic gross appearance, and lack of clinical suspicion. An intraoperative diagnosis of benign struma ovarii enables the general gynecologic surgeon to continue the planned surgery. However, a diagnosis of malignnancy in a struma ovarii would alter the course of surgery with the involvement of a gynecologic oncology surgeon. We present here that our experience with intraoperative consultation for preoperatively undiagnosed struma ovarii presenting as an adnexal cystic or solid mass at our teaching hospital. Fifty-three cases of struma ovarii, 5.2% of all cystic teratoma of the same period, were diagnosed between January 1991 and March 2011. All intraoperative consultation reports, gross descriptions and final pathology reports were reviewed. The H&E stained slides and in selected cases, immunohistochemistry stained slides, were reviewed. Of the 53 cases of struma ovarii, intraoperative consultation was requested on 48 cases. Frozen section was done on 24 cases and only gross examination was felt appropriate in remaining 24 cases. 83% cases were diagnosed when a frozen section was done. None of the remaining 24 cases were recognized as struma by gross inspection. Our findings reveal that in a large number of cases the diagnosis of struma ovarii remained unrecognized during intraoperative consultation, indicating its often subtle/deceptive gross morphologic appearance. However, the purpose of the intraoperative consultation was served, as appropriate information was provided to the surgeon to guide the surgical management.展开更多
Background and Objective: Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems in the U.S., including Veterans. Excessive alcohol use causes neurocognitive and be...Background and Objective: Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems in the U.S., including Veterans. Excessive alcohol use causes neurocognitive and behavioral deficits that can be linked to neurodegeneration. Similarly, preclinical and clinical data suggest that smoking also leads to brain atrophy. This study examines the differential and additive effects of alcohol and cigarette smoke (CS) exposures on cognitive-behavioral function. Methods: A 4-way experimental model of chronic alcohol and CS exposures was generated using 4-week-old male and female Long Evans rats that were pair-fed with Lieber-deCarli isocaloric liquid diets containing 0% or 24% ethanol for 9 weeks. Half of the rats in the control and ethanol groups were exposed to CS for 4 hours/day and 4 days/week for 9 weeks. All rats were subjected to Morris Water Maze, Open Field, and Novel Object Recognition testing in the last experimental week. Results: Chronic alcohol exposure impaired spatial learning as shown by significantly increased latency to locate the platform, and it caused anxiety-like behavior marked by the significantly reduced percentage of entries to the center of the arena. Chronic CS exposure impaired recognition memory as suggested by significantly less time spent at the novel object. Combined exposures to alcohol and CS did not show any significant additive or interactive effect on cognitive-behavioral function. Conclusion: Chronic alcohol exposure was the main driver of spatial learning, while the effect of secondhand CS exposure was not robust. Future studies need to mimic direct CS exposure effects in humans.展开更多
文摘Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.
文摘Struma ovarii often escapes recognition during intraoperative consultation because of its rarity, subtle characteristic gross appearance, and lack of clinical suspicion. An intraoperative diagnosis of benign struma ovarii enables the general gynecologic surgeon to continue the planned surgery. However, a diagnosis of malignnancy in a struma ovarii would alter the course of surgery with the involvement of a gynecologic oncology surgeon. We present here that our experience with intraoperative consultation for preoperatively undiagnosed struma ovarii presenting as an adnexal cystic or solid mass at our teaching hospital. Fifty-three cases of struma ovarii, 5.2% of all cystic teratoma of the same period, were diagnosed between January 1991 and March 2011. All intraoperative consultation reports, gross descriptions and final pathology reports were reviewed. The H&E stained slides and in selected cases, immunohistochemistry stained slides, were reviewed. Of the 53 cases of struma ovarii, intraoperative consultation was requested on 48 cases. Frozen section was done on 24 cases and only gross examination was felt appropriate in remaining 24 cases. 83% cases were diagnosed when a frozen section was done. None of the remaining 24 cases were recognized as struma by gross inspection. Our findings reveal that in a large number of cases the diagnosis of struma ovarii remained unrecognized during intraoperative consultation, indicating its often subtle/deceptive gross morphologic appearance. However, the purpose of the intraoperative consultation was served, as appropriate information was provided to the surgeon to guide the surgical management.
文摘Background and Objective: Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems in the U.S., including Veterans. Excessive alcohol use causes neurocognitive and behavioral deficits that can be linked to neurodegeneration. Similarly, preclinical and clinical data suggest that smoking also leads to brain atrophy. This study examines the differential and additive effects of alcohol and cigarette smoke (CS) exposures on cognitive-behavioral function. Methods: A 4-way experimental model of chronic alcohol and CS exposures was generated using 4-week-old male and female Long Evans rats that were pair-fed with Lieber-deCarli isocaloric liquid diets containing 0% or 24% ethanol for 9 weeks. Half of the rats in the control and ethanol groups were exposed to CS for 4 hours/day and 4 days/week for 9 weeks. All rats were subjected to Morris Water Maze, Open Field, and Novel Object Recognition testing in the last experimental week. Results: Chronic alcohol exposure impaired spatial learning as shown by significantly increased latency to locate the platform, and it caused anxiety-like behavior marked by the significantly reduced percentage of entries to the center of the arena. Chronic CS exposure impaired recognition memory as suggested by significantly less time spent at the novel object. Combined exposures to alcohol and CS did not show any significant additive or interactive effect on cognitive-behavioral function. Conclusion: Chronic alcohol exposure was the main driver of spatial learning, while the effect of secondhand CS exposure was not robust. Future studies need to mimic direct CS exposure effects in humans.
